Loss of Gamma-secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

Overview

Journal J Neurosci

Specialty Neurology

Date 2008 Nov 14

PMID 19005074

Citations 40

Authors

Irfan Y Tamboli

Kai Prager

Dietmar R Thal

Karin M Thelen

Ilse Dewachter

Claus U Pietrzik

Peter St George-Hyslop

Sangram S Sisodia

Bart De Strooper

Michael T Heneka

Mikhail A Filippov

Ulrike Muller

Fred Van Leuven

Dieter Lutjohann

Jochen Walter

Affiliations

Soon will be listed here.

Abstract

Presenilins (PSs) are components of the gamma-secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that gamma-secretase is involved in the regulation of cellular lipoprotein uptake. Loss of gamma-secretase function decreased endocytosis of low-density lipoprotein (LDL) receptor. The decreased uptake of lipoproteins led to upregulation of cellular cholesterol biosynthesis by increased expression of CYP51 and enhanced metabolism of lanosterol. Genetic deletion of PS1 or transgenic expression of PS1 mutants that cause early-onset Alzheimer's disease led to accumulation of gamma-secretase substrates and mistargeting of adaptor proteins that regulate endocytosis of the LDL receptor. Consistent with decreased endocytosis of these receptors, PS1 mutant mice have elevated levels of apolipoprotein E in the brain. Thus, these data demonstrate a functional link between two major genetic factors that cause early-onset and late-onset Alzheimer's disease.

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